This study was designed to examine generally the influence of the gastrointestinal tract upon the insulin response to ingested glucose, and specifically the role of one or more gastrointestinal hormones in the process of insulin secretion. The study is being applied to altered physiologic states, such as aging and obesity, as well as pathologic states of diabetes, and reactive hypoglycemia. It is well established that the response of the endocrine pancreas to ingested nutrients such as glucose is greater than its response to the same stimulus administered intravenously. The physiologic and biochemical etiology of this finding, however, has remained open to debate and investigation. Similarly, the significance of this process in pathologic states is unknown. While gastrointestinal hormones have been suggested as possible mediators of the phenomenon, until recently none has been clearly shown to play a critical role. The development of a sophisticated laboratory technique for studying this process, and the availability of a specific assay for a newly discovered gastrointestinal peptide which appears a likely candidate as the sought-after mediator, have provided the essential means of investigating this process. The present studies show that a specific hormone, gastric inhibitory polypeptide (GIP), responds to oral glucose with a time course in plasma insulin concentration. Furthermore there are significant differences in the physiology of GIP with aging, obesity, and diabetes.